{"gene":"TRIM2","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2008,"finding":"TRIM2 is an UbcH5a-dependent E3 ubiquitin ligase that binds to neurofilament light subunit (NF-L) and regulates NF-L ubiquitination; mice deficient in TRIM2 accumulate NF-L in axons leading to axonopathy and neurodegeneration.","method":"In vitro ubiquitination assay with UbcH5a, co-immunoprecipitation of TRIM2 with NF-L, TRIM2 knockout mouse model with histopathological analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro ubiquitination assay establishing enzymatic activity, direct binding to NF-L by co-IP, and genetic loss-of-function in mice with defined neurodegeneration phenotype; replicated in subsequent papers","pmids":["18687884"],"is_preprint":false},{"year":2010,"finding":"TRIM2 regulates axon specification in hippocampal neurons by ubiquitinating NF-L; RNAi knockdown abolishes neuronal polarity (no axon formed) while overexpression induces multiple axons.","method":"RNA interference knockdown and overexpression in cultured mouse hippocampal neurons with morphological analysis; mechanistic link via NF-L ubiquitination","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss-of-function and gain-of-function with defined morphological phenotype in primary neurons, single lab, mechanistic link to NF-L ubiquitination","pmids":["20796172"],"is_preprint":false},{"year":2011,"finding":"TRIM2 is the E3 ubiquitin ligase that ubiquitinates the pro-apoptotic protein Bim; TRIM2 binds Bim only when Bim is phosphorylated by p42/p44 MAPK (does not interact with nonphosphorylatable 3ABim mutant), and TRIM2 immunodepletion reduces Bim ubiquitination; TRIM2 suppression stabilizes Bim and blocks neuroprotection in rapid ischemic tolerance.","method":"Proteomics/mass spectrometry substrate identification using phospho-GST-Bim as bait, co-immunoprecipitation, immunodepletion assay, lentiviral shRNAmir knockdown in neurons, phosphomutant Bim analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods: MS-based substrate identification, Co-IP confirmation, immunodepletion ubiquitination assay, phosphomutant validation, and functional neuroprotection assay in a single rigorous study","pmids":["21478148"],"is_preprint":false},{"year":2013,"finding":"Loss-of-function compound heterozygous mutations in TRIM2 cause early-onset axonal neuropathy in humans, with absence of TRIM2 protein leading to axonal accumulation of neurofilaments, consistent with the mouse Trim2 gene-trap model.","method":"Whole-exome sequencing, mRNA/protein stability analysis in patient fibroblasts, sural nerve biopsy histopathology, comparison with Trim2 gene-trap mouse model","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetics combined with patient cell and mouse model data, single study confirming mechanistic link between TRIM2 loss and NF-L accumulation","pmids":["23562820"],"is_preprint":false},{"year":2017,"finding":"TRIM2 acts downstream of GPER-activated MAPK/ERK signaling to ubiquitinate and degrade Bim, contributing to tamoxifen resistance in ER+ breast cancer cells; MAPK/ERK (not PI3K/AKT) activation increases TRIM2 levels and enhances TRIM2–Bim binding.","method":"Co-immunoprecipitation, Western blot, Bim overexpression/knockdown in MCF-7 and MCF-7R cells, pathway inhibitor studies","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP of TRIM2–Bim interaction confirmed, pathway dissection with inhibitors, single lab","pmids":["28902352"],"is_preprint":false},{"year":2019,"finding":"TRIM2 restricts New World arenavirus (Junín, Tacaribe) entry into cells; this antiviral activity is independent of the RING domain (ubiquitin ligase activity). TRIM2 interacts with SIRPA (signal regulatory protein α), a known inhibitor of phagocytosis, and TRIM2 limits phagocytosis of apoptotic cells.","method":"Trim2-knockout mice and patient fibroblasts challenged with NWA, TRIM2 RING-domain mutant constructs, interactome analysis identifying SIRPA, phagocytosis assays","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic KO in mice, patient-derived cells, domain-deletion mutants, and interactome data using multiple orthogonal approaches in one study","pmids":["30726215"],"is_preprint":false},{"year":2020,"finding":"TRIM2 interacts with and deubiquitinates/stabilizes Snail1 protein in lung adenocarcinoma cells, reducing Snail1 ubiquitination-dependent degradation and promoting EMT, proliferation, and invasion.","method":"Co-immunoprecipitation, Western blot, ubiquitination assay, TRIM2 overexpression and knockdown in lung adenocarcinoma cell lines","journal":"Cancer cell international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Co-IP and Western blot only; the deubiquitination claim for a RING E3 ligase is mechanistically unusual and not validated by orthogonal methods","pmids":["32536816"],"is_preprint":false},{"year":2020,"finding":"In Xenopus, TRIM2 interacts with ALIX (ALG-2 interacting protein X) of the ESCRT complex; trim2 morphant embryos show clustering and apoptosis of neural progenitors phenocopying Alix KO, suggesting TRIM2–ALIX interaction regulates neural progenitor survival during neurogenesis.","method":"GST-Trim2 pulldown from Xenopus embryonic lysates with LC-MS/MS identification of ALIX, co-expression analysis, morpholino knockdown with phenotypic characterization","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — MS-based pulldown identification of ALIX, morpholino loss-of-function with defined neural phenotype, single lab","pmids":["32698497"],"is_preprint":false},{"year":2020,"finding":"Trim2-null (CRISPR-Cas9) mice develop axonal neuropathy with NF-L accumulation in axons; a separate partial RING-domain deletion strain (Trim2C/C) with reduced ubiquitination activity does not recapitulate this neuropathy, suggesting the axonopathy may not require full ubiquitin ligase activity.","method":"CRISPR-Cas9 knockout mice, histopathology of multiple neuronal populations, comparison of two Trim2 mutant alleles with different domain deletions","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic comparison of two alleles in vivo with detailed neuropathological characterization, single lab","pmids":["32205255"],"is_preprint":false},{"year":2022,"finding":"The RING domain of human TRIM3 (TRIM2 paralog) is monomeric and inactive due to placental mammal-specific amino acid changes that prevent self-association but not E2 recognition; TRIM3 activity is restored by substituting the relevant region with TRIM2 sequence or by heterodimerization with TRIM2. TRIM2 and TRIM3 interact in cells via their filamin and coiled-coil domains, respectively.","method":"Crystal structure / structure-function analysis of RING domains, mutagenesis, in vitro E3 ligase assays, cellular co-immunoprecipitation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural analysis combined with mutagenesis and in vitro enzymatic reconstitution plus cellular Co-IP, multiple orthogonal methods in a single rigorous study","pmids":["36481767"],"is_preprint":false},{"year":2022,"finding":"TRIM2 promotes p53 ubiquitination and degradation in colorectal cancer cells; CEBPB acts as an upstream transcription factor that binds the TRIM2 promoter and drives its expression in response to epinephrine, linking stress signaling to p53 stability.","method":"Chromatin immunoprecipitation (ChIP) for CEBPB binding to TRIM2 promoter, co-immunoprecipitation of TRIM2 with p53, ubiquitination assay, transcriptome sequencing","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — ChIP confirms CEBPB–TRIM2 promoter interaction, Co-IP confirms TRIM2–p53 binding and ubiquitination, single lab","pmids":["35672760"],"is_preprint":false},{"year":2024,"finding":"TRIM2 specifically interacts with CPT1A (carnitine O-palmitoyltransferase 1, the rate-limiting enzyme of fatty acid oxidation) and enhances its enzymatic activity, thereby regulating intracellular lipid levels and protecting cancer cells from glutamine deprivation-induced apoptosis; TRIM2 expression in this context is induced by ATF4.","method":"Co-immunoprecipitation of TRIM2 with CPT1A, CPT1A enzymatic activity assay, lipid level measurement, TRIM2 knockdown/overexpression with apoptosis and proliferation assays, xenograft tumor growth","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirms interaction, enzymatic activity assay establishes functional enhancement of CPT1A, in vivo xenograft validation, single lab","pmids":["38949993"],"is_preprint":false},{"year":2024,"finding":"TRIM2 interacts with CYP11B2 (aldosterone synthase) via its RBCC domain and promotes K29/K48-linked polyubiquitination and proteasomal degradation of CYP11B2, thereby reducing aldosterone production in adrenal tumor cells.","method":"siRNA E3 ligase screen, co-immunoprecipitation of TRIM2 with CYP11B2, ubiquitination assay specifying K29/K48 linkages, overexpression assays in adrenal tumor cells measuring aldosterone levels","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirms TRIM2–CYP11B2 interaction, ubiquitination assay defines linkage type, functional readout of aldosterone, single lab","pmids":["39725733"],"is_preprint":false},{"year":2024,"finding":"TRIM2 knockdown in endothelial cells attenuates inflammation-driven (but not hypoxia-driven) angiogenesis by reducing nuclear HIF-1α accumulation and downstream eNOS phosphorylation; Trim2-/- mice show reduced adventitial neovascularization in an inflammation model but not in hindlimb ischemia.","method":"CRISPR/Cas9 Trim2-/- mice in periarterial collar and hindlimb ischemia models, lentiviral shRNA knockdown in endothelial cells, HIF-1α nuclear fractionation, eNOS phosphorylation Western blot","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in two distinct mouse models plus in vitro mechanistic dissection, single lab","pmids":["38542330"],"is_preprint":false},{"year":2025,"finding":"TRIM2 directly interacts with the pro-apoptotic protein BNIP3 and mediates K48-linked polyubiquitination of BNIP3 at lysine 130 (K130), targeting it for proteasomal degradation; mutation K130R abolishes TRIM2-mediated ubiquitination, stabilizes BNIP3, and increases cell death; this TRIM2–BNIP3 axis protects against intestinal ischemia-reperfusion injury.","method":"Co-immunoprecipitation of TRIM2 with BNIP3, site-directed mutagenesis (K130R), ubiquitination assay specifying K48 linkage, TRIM2 genetic deletion mouse model, hypoxia/reoxygenation cell death assay","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — Co-IP confirms direct interaction, mutagenesis identifies exact ubiquitination site, K48-linkage specificity established, genetic KO mouse confirms in vivo relevance; multiple orthogonal methods in one study","pmids":["40883557"],"is_preprint":false},{"year":2026,"finding":"Using ubiquitin-specific proximity labeling in cells, TRIM2 was found to target proteins of the endolysosomal pathway; specifically, TRIM2 ubiquitinates TMEM106B at lysine residues in its cytosolic N-terminal region. Substrate recognition involves a direct interaction between TRIM2 and a zinc-coordination motif in TMEM106B that mediates homodimerization and is required for lysosomal size regulation. The tripartite motif of TRIM2 (beyond the RING) contributes to substrate recruitment.","method":"Ubiquitin-specific proximity labeling (UbID), biochemical pulldown, structural studies, site-directed mutagenesis of TMEM106B lysine residues, lysosomal size assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — proximity labeling substrate discovery combined with structural and biochemical validation plus mutagenesis of ubiquitination sites, multiple orthogonal methods","pmids":["41484378"],"is_preprint":false},{"year":2025,"finding":"TRIM2 knockdown and overexpression in primary neurons regulate NF-L protein levels and α-synuclein aggregation, suggesting TRIM2 modulates both substrates relevant to Parkinson's disease neuropathology.","method":"Lentiviral knockdown and overexpression in primary neurons, measurement of NF-L levels and α-synuclein aggregation; peripheral proteomic analysis showing increased plasma/CSF NF-L in TRIM2 SNP carriers","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, primary neuron functional assays without in vitro reconstitution, single study with limited mechanistic detail in abstract","pmids":["bio_10.1101_2025.02.21.25322301"],"is_preprint":true},{"year":2025,"finding":"TRIM2 is an m6A-modified substrate of YTHDF3; TRIM2 interacts with and ubiquitinates p53, promoting its degradation via the ubiquitin-proteasome system in uveal melanoma cells.","method":"RIP-qPCR confirming m6A modification of TRIM2 by YTHDF3, co-immunoprecipitation of TRIM2 with p53, cycloheximide chase assay demonstrating TRIM2-mediated p53 degradation","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RIP-qPCR for m6A modification, Co-IP for TRIM2–p53 interaction, CHX chase for functional degradation, single lab","pmids":["41391676"],"is_preprint":false},{"year":2014,"finding":"Crystallization of the C-terminal NHL domain of human TRIM2 (residues 465–744) yielded crystals diffracting to 1.7 Å resolution (space group P21), enabling structural characterization of this substrate-recognition domain.","method":"Recombinant protein expression/purification, X-ray crystallography, molecular replacement phasing","journal":"Acta crystallographica. Section F, Structural biology communications","confidence":"Low","confidence_rationale":"Tier 1 / Weak — crystal structure reported as preliminary (no functional validation of NHL domain function described in abstract, no mutagenesis)","pmids":["24817735"],"is_preprint":false}],"current_model":"TRIM2 is a RING-type E3 ubiquitin ligase that requires UbcH5a as its E2 and functions primarily in neurons, where it ubiquitinates neurofilament light chain (NF-L) to control axonal NF-L levels and neuronal polarity, and ubiquitinates the pro-apoptotic proteins Bim (in a p42/p44 MAPK phosphorylation-dependent manner), BNIP3 (K48-linked at K130), p53, and CYP11B2, as well as the endolysosomal protein TMEM106B; its RING domain dimerization is required for ligase activity, and it possesses a separate antiviral function against New World arenaviruses that is RING-domain independent and mediated partly through interaction with SIRPA."},"narrative":{"mechanistic_narrative":"TRIM2 is a RING-type E3 ubiquitin ligase that uses UbcH5a as its cognate E2 and functions prominently in neurons, where it binds and ubiquitinates neurofilament light chain (NF-L) to control axonal NF-L levels, neuronal polarity, and axon specification [PMID:18687884, PMID:20796172]; loss of TRIM2 in mice and in humans with biallelic loss-of-function mutations causes early-onset axonal neuropathy with neurofilament accumulation [PMID:18687884, PMID:23562820]. Its catalytic competence depends on RING-domain self-association, which a placental-mammal-specific divergence has abolished in the paralog TRIM3, restorable by heterodimerization with TRIM2 through their filamin and coiled-coil domains [PMID:36481767]. Beyond NF-L, TRIM2 directs ubiquitin-dependent degradation of multiple pro-apoptotic and signaling substrates: it ubiquitinates Bim selectively when Bim is phosphorylated by p42/p44 MAPK, coupling survival signaling to apoptotic control in neuroprotection and tamoxifen-resistant breast cancer [PMID:21478148, PMID:28902352]; it mediates K48-linked ubiquitination of BNIP3 at K130 to protect against ischemia-reperfusion injury [PMID:40883557]; it promotes p53 ubiquitination and degradation [PMID:35672760, PMID:41391676]; it drives K29/K48-linked degradation of the aldosterone synthase CYP11B2 [PMID:39725733]; and it ubiquitinates the endolysosomal protein TMEM106B at cytosolic N-terminal lysines, with substrate recognition mediated by the tripartite motif beyond the RING and by a zinc-coordination motif in TMEM106B that controls lysosomal size [PMID:41484378]. TRIM2 also possesses a RING-independent antiviral activity that restricts New World arenavirus entry and interacts with SIRPA to limit phagocytosis of apoptotic cells [PMID:30726215], and it engages the ESCRT component ALIX to regulate neural progenitor survival [PMID:32698497]. Non-degradative or non-canonical activities have also been described, including stabilization of CPT1A to support fatty acid oxidation [PMID:38949993].","teleology":[{"year":2008,"claim":"Established TRIM2 as a bona fide E3 ubiquitin ligase and identified NF-L as its substrate, defining a molecular basis for axonal maintenance.","evidence":"in vitro ubiquitination with UbcH5a, NF-L co-IP, and TRIM2-knockout mice with axonopathy","pmids":["18687884"],"confidence":"High","gaps":["Ubiquitin linkage type on NF-L not defined","Whether NF-L degradation is proteasomal not directly shown"]},{"year":2010,"claim":"Connected TRIM2-mediated NF-L ubiquitination to the cell-biological decision of axon specification and neuronal polarity.","evidence":"RNAi knockdown and overexpression in cultured hippocampal neurons with morphological scoring","pmids":["20796172"],"confidence":"Medium","gaps":["Single lab","Mechanism linking NF-L turnover to polarity not resolved"]},{"year":2011,"claim":"Identified Bim as a phosphorylation-gated TRIM2 substrate, coupling MAPK survival signaling to apoptotic regulation in neuroprotection.","evidence":"MS substrate ID with phospho-Bim bait, immunodepletion ubiquitination, phosphomutant analysis, neuronal shRNA","pmids":["21478148"],"confidence":"High","gaps":["Ubiquitin linkage on Bim not characterized","Structural basis of phospho-dependent recognition unknown"]},{"year":2013,"claim":"Demonstrated that TRIM2 loss causes a human Mendelian axonal neuropathy, validating the mouse model in patients.","evidence":"whole-exome sequencing, patient fibroblast protein analysis, sural nerve biopsy","pmids":["23562820"],"confidence":"Medium","gaps":["Single study","Genotype-phenotype range not established"]},{"year":2017,"claim":"Extended the TRIM2-Bim axis to cancer, showing GPER/MAPK-driven TRIM2 expression degrades Bim to confer tamoxifen resistance.","evidence":"Co-IP, pathway inhibitor dissection, and Bim manipulation in MCF-7/MCF-7R cells","pmids":["28902352"],"confidence":"Medium","gaps":["Single lab","Direct ubiquitination in this context not shown"]},{"year":2019,"claim":"Revealed a RING-independent function: TRIM2 restricts New World arenavirus entry and interacts with SIRPA to limit phagocytosis, separating its antiviral role from ligase activity.","evidence":"Trim2-KO mice and patient fibroblasts, RING-domain mutants, interactome, phagocytosis assays","pmids":["30726215"],"confidence":"High","gaps":["Molecular mechanism of viral entry restriction unresolved","Whether SIRPA is a ubiquitination substrate unknown"]},{"year":2020,"claim":"Linked TRIM2 to ESCRT machinery via ALIX in neural progenitor survival during neurogenesis.","evidence":"GST-Trim2 pulldown with LC-MS/MS in Xenopus and morpholino phenotyping","pmids":["32698497"],"confidence":"Medium","gaps":["Single lab and model organism","Whether ALIX is a substrate or partner not resolved"]},{"year":2020,"claim":"Reported an unusual deubiquitinating/stabilizing effect of TRIM2 on Snail1 promoting EMT in lung adenocarcinoma.","evidence":"Co-IP, Western blot, and ubiquitination assay in lung cancer cell lines","pmids":["32536816"],"confidence":"Low","gaps":["Deubiquitination claim for a RING E3 is mechanistically unusual and not validated by orthogonal methods","No reciprocal validation"]},{"year":2020,"claim":"Genetic allele comparison suggested the axonopathy phenotype may not require full ligase activity, complicating the catalytic model.","evidence":"CRISPR Trim2-null versus partial RING-deletion mouse strains with neuropathology","pmids":["32205255"],"confidence":"Medium","gaps":["Residual ligase activity in deletion allele not quantified mechanistically","Single lab"]},{"year":2022,"claim":"Structurally explained TRIM2 RING-dimerization dependence and showed TRIM2 can restore the inactive paralog TRIM3 via heterodimerization.","evidence":"RING domain structure-function, mutagenesis, in vitro E3 assays, cellular Co-IP","pmids":["36481767"],"confidence":"High","gaps":["Functional consequences of TRIM2-TRIM3 heterodimers in vivo not defined"]},{"year":2022,"claim":"Placed TRIM2 in a stress-signaling axis where CEBPB drives TRIM2 expression to degrade p53 in colorectal cancer.","evidence":"ChIP for CEBPB-promoter binding, Co-IP, ubiquitination assay, RNA-seq","pmids":["35672760"],"confidence":"Medium","gaps":["Ubiquitin linkage on p53 not defined","Single lab"]},{"year":2024,"claim":"Identified a non-degradative metabolic role: TRIM2 binds and enhances CPT1A activity to support fatty acid oxidation and survival under glutamine deprivation.","evidence":"Co-IP, CPT1A activity and lipid assays, xenograft growth, ATF4 induction","pmids":["38949993"],"confidence":"Medium","gaps":["Mechanism of enzymatic enhancement unknown","Whether ubiquitination is involved unresolved"]},{"year":2024,"claim":"Defined TRIM2 control of aldosterone synthesis via K29/K48-linked degradation of CYP11B2.","evidence":"siRNA E3 screen, Co-IP, linkage-specific ubiquitination, aldosterone measurement in adrenal tumor cells","pmids":["39725733"],"confidence":"Medium","gaps":["Single lab","Physiological regulation of this axis not established"]},{"year":2024,"claim":"Demonstrated a context-specific vascular role for TRIM2 in inflammation-driven angiogenesis through HIF-1α and eNOS signaling.","evidence":"Trim2-/- mice in two models, endothelial shRNA, HIF-1α fractionation, eNOS phosphorylation","pmids":["38542330"],"confidence":"Medium","gaps":["Direct substrate in endothelial cells not identified","Single lab"]},{"year":2025,"claim":"Resolved a precise degron, identifying K48-linked ubiquitination of BNIP3 at K130 as a protective axis in intestinal ischemia-reperfusion.","evidence":"Co-IP, K130R mutagenesis, K48-linkage ubiquitination assay, KO mouse, hypoxia/reoxygenation death assay","pmids":["40883557"],"confidence":"High","gaps":["Whether this axis operates in non-intestinal tissues unknown"]},{"year":2025,"claim":"Connected TRIM2 to m6A regulation (YTHDF3) and reaffirmed p53 as a degradation substrate in uveal melanoma.","evidence":"RIP-qPCR for m6A, Co-IP, cycloheximide chase","pmids":["41391676"],"confidence":"Medium","gaps":["Ubiquitin linkage on p53 not specified","Single lab"]},{"year":2026,"claim":"Used unbiased proximity labeling to place TRIM2 in the endolysosomal pathway, identifying TMEM106B as a substrate and defining tripartite-motif-mediated, structure-based substrate recognition.","evidence":"ubiquitin-specific proximity labeling, biochemical pulldown, structural studies, TMEM106B lysine mutagenesis, lysosomal size assays","pmids":["41484378"],"confidence":"High","gaps":["Linkage type on TMEM106B not detailed","Physiological role in lysosomal regulation in vivo not established"]},{"year":null,"claim":"It remains unresolved how TRIM2 selects among its diverse substrates across neurons, immune cells, endothelium, and tumors, and how its RING-dependent ligase activity, RING-independent antiviral function, and non-degradative metabolic roles are coordinated within a single protein.","evidence":"no single study integrates the divergent functional contexts","pmids":[],"confidence":"Low","gaps":["No unifying model of substrate selection","Tissue-specific cofactors unknown","Relationship between catalytic and non-catalytic functions undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,12,14,15]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,12,14]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,14,15]},{"term_id":"GO:0031386","term_label":"protein tag activity","supporting_discovery_ids":[14,15]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,15]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,12,14,15]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5]}],"complexes":[],"partners":["NEFL","BCL2L11","BNIP3","TP53","CYP11B2","TMEM106B","SIRPA","CPT1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9C040","full_name":"Tripartite motif-containing protein 2","aliases":["E3 ubiquitin-protein ligase TRIM2","RING finger protein 86","RING-type E3 ubiquitin transferase TRIM2"],"length_aa":744,"mass_kda":81.5,"function":"UBE2D1-dependent E3 ubiquitin-protein ligase that mediates the ubiquitination of NEFL and of phosphorylated BCL2L11. Plays a neuroprotective function. May play a role in neuronal rapid ischemic tolerance. Plays a role in antiviral immunity and limits New World arenavirus infection independently of its ubiquitin ligase activity (PubMed:24068738)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9C040/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRIM2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TRIM2","total_profiled":1310},"omim":[{"mim_id":"615490","title":"CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2R; CMT2R","url":"https://www.omim.org/entry/615490"},{"mim_id":"614141","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 2; TRIM2","url":"https://www.omim.org/entry/614141"},{"mim_id":"603827","title":"BCL2-LIKE 11; BCL2L11","url":"https://www.omim.org/entry/603827"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Centrosome","reliability":"Uncertain"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":62.9}],"url":"https://www.proteinatlas.org/search/TRIM2"},"hgnc":{"alias_symbol":["KIAA0517","RNF86","CMT2R"],"prev_symbol":[]},"alphafold":{"accession":"Q9C040","domains":[{"cath_id":"3.30.40.10","chopping":"10-94_102-115","consensus_level":"medium","plddt":76.0169,"start":10,"end":115},{"cath_id":"-","chopping":"158-291","consensus_level":"high","plddt":91.7816,"start":158,"end":291},{"cath_id":"2.60.40.10","chopping":"325-423","consensus_level":"high","plddt":87.7988,"start":325,"end":423},{"cath_id":"2.120.10.30","chopping":"473-741","consensus_level":"medium","plddt":95.021,"start":473,"end":741}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C040","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C040-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C040-F1-predicted_aligned_error_v6.png","plddt_mean":84.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRIM2","jax_strain_url":"https://www.jax.org/strain/search?query=TRIM2"},"sequence":{"accession":"Q9C040","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9C040.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9C040/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C040"}},"corpus_meta":[{"pmid":"18687884","id":"PMC_18687884","title":"Deficiency in ubiquitin ligase TRIM2 causes accumulation of neurofilament light chain and neurodegeneration.","date":"2008","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/18687884","citation_count":123,"is_preprint":false},{"pmid":"23562820","id":"PMC_23562820","title":"Deficiency of the E3 ubiquitin ligase TRIM2 in early-onset axonal neuropathy.","date":"2013","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23562820","citation_count":61,"is_preprint":false},{"pmid":"35672760","id":"PMC_35672760","title":"Stress-induced epinephrine promotes epithelial-to-mesenchymal transition and stemness of CRC through the CEBPB/TRIM2/P53 axis.","date":"2022","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35672760","citation_count":56,"is_preprint":false},{"pmid":"28902352","id":"PMC_28902352","title":"GPER promotes tamoxifen-resistance in ER+ breast cancer cells by reduced Bim proteins through MAPK/Erk-TRIM2 signaling axis.","date":"2017","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28902352","citation_count":54,"is_preprint":false},{"pmid":"21478148","id":"PMC_21478148","title":"Identification of a novel Bcl-2-interacting mediator of cell death (Bim) E3 ligase, tripartite motif-containing protein 2 (TRIM2), and its role in rapid ischemic tolerance-induced neuroprotection.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21478148","citation_count":51,"is_preprint":false},{"pmid":"26472353","id":"PMC_26472353","title":"MicroRNA-145 targets TRIM2 and exerts tumor-suppressing functions in epithelial ovarian cancer.","date":"2015","source":"Gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/26472353","citation_count":42,"is_preprint":false},{"pmid":"20796172","id":"PMC_20796172","title":"The E3-ubiquitin ligase TRIM2 regulates neuronal polarization.","date":"2010","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20796172","citation_count":39,"is_preprint":false},{"pmid":"32929153","id":"PMC_32929153","title":"Oncogenic function of TRIM2 in pancreatic cancer by activating ROS-related NRF2/ITGB7/FAK axis.","date":"2020","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/32929153","citation_count":35,"is_preprint":false},{"pmid":"32536816","id":"PMC_32536816","title":"TRIM2 directly deubiquitinates and stabilizes Snail1 protein, mediating proliferation and metastasis of lung adenocarcinoma.","date":"2020","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/32536816","citation_count":28,"is_preprint":false},{"pmid":"30066883","id":"PMC_30066883","title":"TRIM2 regulates the development and metastasis of tumorous cells of osteosarcoma.","date":"2018","source":"International journal of 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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33760118","citation_count":23,"is_preprint":false},{"pmid":"37499712","id":"PMC_37499712","title":"Genome-scale CRISPR screen identifies TRIM2 and SLC35A1 associated with porcine epidemic diarrhoea virus infection.","date":"2023","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/37499712","citation_count":22,"is_preprint":false},{"pmid":"30916596","id":"PMC_30916596","title":"TRIM2 is a novel promoter of human colorectal cancer.","date":"2019","source":"Scandinavian journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/30916596","citation_count":21,"is_preprint":false},{"pmid":"25893792","id":"PMC_25893792","title":"Exome sequencing reveals homozygous TRIM2 mutation in a patient with early onset CMT and bilateral vocal cord paralysis.","date":"2015","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25893792","citation_count":21,"is_preprint":false},{"pmid":"36051486","id":"PMC_36051486","title":"Expression and Role of TRIM2 in Human Diseases.","date":"2022","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/36051486","citation_count":20,"is_preprint":false},{"pmid":"36481767","id":"PMC_36481767","title":"Divergent self-association properties of paralogous proteins TRIM2 and TRIM3 regulate their E3 ligase activity.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36481767","citation_count":18,"is_preprint":false},{"pmid":"32205255","id":"PMC_32205255","title":"A recessive Trim2 mutation causes an axonal neuropathy in mice.","date":"2020","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/32205255","citation_count":16,"is_preprint":false},{"pmid":"33378023","id":"PMC_33378023","title":"Long non-coding RNA NR2F1-AS1 promoted neuroblastoma progression through miR-493-5p/TRIM2 axis.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33378023","citation_count":16,"is_preprint":false},{"pmid":"29958463","id":"PMC_29958463","title":"Exploring the Roles of CREBRF and TRIM2 in the Regulation of Angiogenesis by High-Density Lipoproteins.","date":"2018","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29958463","citation_count":16,"is_preprint":false},{"pmid":"32698497","id":"PMC_32698497","title":"Interplay of TRIM2 E3 Ubiquitin Ligase and ALIX/ESCRT Complex: Control of Developmental Plasticity During Early Neurogenesis.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/32698497","citation_count":10,"is_preprint":false},{"pmid":"35342411","id":"PMC_35342411","title":"LINC01535 Attenuates ccRCC Progression through Regulation of the miR-146b-5p/TRIM2 Axis and Inactivation of the PI3K/Akt Pathway.","date":"2022","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35342411","citation_count":10,"is_preprint":false},{"pmid":"38949993","id":"PMC_38949993","title":"TRIM2 promotes metabolic adaptation to glutamine deprivation via enhancement of CPT1A activity.","date":"2024","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/38949993","citation_count":9,"is_preprint":false},{"pmid":"32815244","id":"PMC_32815244","title":"Expanding the phenotypic spectrum of TRIM2-associated Charcot-Marie-Tooth disease.","date":"2020","source":"Journal of the peripheral nervous system : JPNS","url":"https://pubmed.ncbi.nlm.nih.gov/32815244","citation_count":6,"is_preprint":false},{"pmid":"38542330","id":"PMC_38542330","title":"TRIM2 Selectively Regulates Inflammation-Driven Pathological Angiogenesis without Affecting Physiological Hypoxia-Mediated Angiogenesis.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38542330","citation_count":4,"is_preprint":false},{"pmid":"36920626","id":"PMC_36920626","title":"Hsa_circ_0001361 facilitates cell progression and glycolytic metabolism in neuroblastoma via interacting with mir-490-5p to induce TRIM2 upregulation.","date":"2023","source":"Metabolic brain disease","url":"https://pubmed.ncbi.nlm.nih.gov/36920626","citation_count":4,"is_preprint":false},{"pmid":"38946721","id":"PMC_38946721","title":"CircORC2 promoted proliferation and inhibited the sensitivity of osteosarcoma cell lines to cisplatin by regulating the miR-485-3p/TRIM2 axis.","date":"2024","source":"Journal of cell communication and signaling","url":"https://pubmed.ncbi.nlm.nih.gov/38946721","citation_count":3,"is_preprint":false},{"pmid":"24817735","id":"PMC_24817735","title":"Expression, purification, crystallization and preliminary X-ray diffraction analysis of the C-terminal NHL domain of human TRIM2.","date":"2014","source":"Acta crystallographica. Section F, Structural biology communications","url":"https://pubmed.ncbi.nlm.nih.gov/24817735","citation_count":2,"is_preprint":false},{"pmid":"39725733","id":"PMC_39725733","title":"E3 ubiquitin ligase TRIM2 identified as a novel suppressor of CYP11B2 and aldosterone production.","date":"2024","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/39725733","citation_count":1,"is_preprint":false},{"pmid":"40946588","id":"PMC_40946588","title":"Curcumin suppresses colorectal cancer by inhibiting TRIM2 and mTOR signaling.","date":"2025","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40946588","citation_count":1,"is_preprint":false},{"pmid":"41484378","id":"PMC_41484378","title":"TRIM2 E3 ligase substrate discovery reveals zinc-mediated regulation of TMEM106B in the endolysosomal pathway.","date":"2026","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/41484378","citation_count":1,"is_preprint":false},{"pmid":"40883557","id":"PMC_40883557","title":"TRIM2 inhibits apoptosis by ubiquitinating BNIP3 to protect the intestine against ischemia-reperfusion injury in mice.","date":"2025","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/40883557","citation_count":0,"is_preprint":false},{"pmid":"41413621","id":"PMC_41413621","title":"TRIM2 exacerbates the advancement of idiopathic pulmonary fibrosis by modulating β-catenin and endoplasmic reticulum stress.","date":"2025","source":"European journal of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/41413621","citation_count":0,"is_preprint":false},{"pmid":"41391676","id":"PMC_41391676","title":"YTHDF3-TRIM2-P53 axis promotes malignant progression in uveal melanoma (UVM).","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/41391676","citation_count":0,"is_preprint":false},{"pmid":"41918119","id":"PMC_41918119","title":"Integrated multi-omics analysis and functional validation reveal the role of TRIM2 as a potential novel biomarker in breast cancer.","date":"2026","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/41918119","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.21.25322301","title":"Progression GWAS followed by functional characterization implicates E3 ubiquitin ligase<i>TRIM2</i>as a potential genetic modifier of Parkinson’s disease progression","date":"2025-02-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.21.25322301","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.13.682210","title":"Structure-function relationship of alpha-synuclein fibrillar polymorphs derived from distinct synucleinopathies","date":"2025-10-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.13.682210","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21185,"output_tokens":4996,"usd":0.069248,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13309,"output_tokens":4711,"usd":0.09216,"stage2_stop_reason":"end_turn"},"total_usd":0.161408,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"TRIM2 is an UbcH5a-dependent E3 ubiquitin ligase that binds to neurofilament light subunit (NF-L) and regulates NF-L ubiquitination; mice deficient in TRIM2 accumulate NF-L in axons leading to axonopathy and neurodegeneration.\",\n      \"method\": \"In vitro ubiquitination assay with UbcH5a, co-immunoprecipitation of TRIM2 with NF-L, TRIM2 knockout mouse model with histopathological analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro ubiquitination assay establishing enzymatic activity, direct binding to NF-L by co-IP, and genetic loss-of-function in mice with defined neurodegeneration phenotype; replicated in subsequent papers\",\n      \"pmids\": [\"18687884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TRIM2 regulates axon specification in hippocampal neurons by ubiquitinating NF-L; RNAi knockdown abolishes neuronal polarity (no axon formed) while overexpression induces multiple axons.\",\n      \"method\": \"RNA interference knockdown and overexpression in cultured mouse hippocampal neurons with morphological analysis; mechanistic link via NF-L ubiquitination\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss-of-function and gain-of-function with defined morphological phenotype in primary neurons, single lab, mechanistic link to NF-L ubiquitination\",\n      \"pmids\": [\"20796172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TRIM2 is the E3 ubiquitin ligase that ubiquitinates the pro-apoptotic protein Bim; TRIM2 binds Bim only when Bim is phosphorylated by p42/p44 MAPK (does not interact with nonphosphorylatable 3ABim mutant), and TRIM2 immunodepletion reduces Bim ubiquitination; TRIM2 suppression stabilizes Bim and blocks neuroprotection in rapid ischemic tolerance.\",\n      \"method\": \"Proteomics/mass spectrometry substrate identification using phospho-GST-Bim as bait, co-immunoprecipitation, immunodepletion assay, lentiviral shRNAmir knockdown in neurons, phosphomutant Bim analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods: MS-based substrate identification, Co-IP confirmation, immunodepletion ubiquitination assay, phosphomutant validation, and functional neuroprotection assay in a single rigorous study\",\n      \"pmids\": [\"21478148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss-of-function compound heterozygous mutations in TRIM2 cause early-onset axonal neuropathy in humans, with absence of TRIM2 protein leading to axonal accumulation of neurofilaments, consistent with the mouse Trim2 gene-trap model.\",\n      \"method\": \"Whole-exome sequencing, mRNA/protein stability analysis in patient fibroblasts, sural nerve biopsy histopathology, comparison with Trim2 gene-trap mouse model\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetics combined with patient cell and mouse model data, single study confirming mechanistic link between TRIM2 loss and NF-L accumulation\",\n      \"pmids\": [\"23562820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRIM2 acts downstream of GPER-activated MAPK/ERK signaling to ubiquitinate and degrade Bim, contributing to tamoxifen resistance in ER+ breast cancer cells; MAPK/ERK (not PI3K/AKT) activation increases TRIM2 levels and enhances TRIM2–Bim binding.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, Bim overexpression/knockdown in MCF-7 and MCF-7R cells, pathway inhibitor studies\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP of TRIM2–Bim interaction confirmed, pathway dissection with inhibitors, single lab\",\n      \"pmids\": [\"28902352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM2 restricts New World arenavirus (Junín, Tacaribe) entry into cells; this antiviral activity is independent of the RING domain (ubiquitin ligase activity). TRIM2 interacts with SIRPA (signal regulatory protein α), a known inhibitor of phagocytosis, and TRIM2 limits phagocytosis of apoptotic cells.\",\n      \"method\": \"Trim2-knockout mice and patient fibroblasts challenged with NWA, TRIM2 RING-domain mutant constructs, interactome analysis identifying SIRPA, phagocytosis assays\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic KO in mice, patient-derived cells, domain-deletion mutants, and interactome data using multiple orthogonal approaches in one study\",\n      \"pmids\": [\"30726215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM2 interacts with and deubiquitinates/stabilizes Snail1 protein in lung adenocarcinoma cells, reducing Snail1 ubiquitination-dependent degradation and promoting EMT, proliferation, and invasion.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, ubiquitination assay, TRIM2 overexpression and knockdown in lung adenocarcinoma cell lines\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Co-IP and Western blot only; the deubiquitination claim for a RING E3 ligase is mechanistically unusual and not validated by orthogonal methods\",\n      \"pmids\": [\"32536816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In Xenopus, TRIM2 interacts with ALIX (ALG-2 interacting protein X) of the ESCRT complex; trim2 morphant embryos show clustering and apoptosis of neural progenitors phenocopying Alix KO, suggesting TRIM2–ALIX interaction regulates neural progenitor survival during neurogenesis.\",\n      \"method\": \"GST-Trim2 pulldown from Xenopus embryonic lysates with LC-MS/MS identification of ALIX, co-expression analysis, morpholino knockdown with phenotypic characterization\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — MS-based pulldown identification of ALIX, morpholino loss-of-function with defined neural phenotype, single lab\",\n      \"pmids\": [\"32698497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Trim2-null (CRISPR-Cas9) mice develop axonal neuropathy with NF-L accumulation in axons; a separate partial RING-domain deletion strain (Trim2C/C) with reduced ubiquitination activity does not recapitulate this neuropathy, suggesting the axonopathy may not require full ubiquitin ligase activity.\",\n      \"method\": \"CRISPR-Cas9 knockout mice, histopathology of multiple neuronal populations, comparison of two Trim2 mutant alleles with different domain deletions\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic comparison of two alleles in vivo with detailed neuropathological characterization, single lab\",\n      \"pmids\": [\"32205255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The RING domain of human TRIM3 (TRIM2 paralog) is monomeric and inactive due to placental mammal-specific amino acid changes that prevent self-association but not E2 recognition; TRIM3 activity is restored by substituting the relevant region with TRIM2 sequence or by heterodimerization with TRIM2. TRIM2 and TRIM3 interact in cells via their filamin and coiled-coil domains, respectively.\",\n      \"method\": \"Crystal structure / structure-function analysis of RING domains, mutagenesis, in vitro E3 ligase assays, cellular co-immunoprecipitation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural analysis combined with mutagenesis and in vitro enzymatic reconstitution plus cellular Co-IP, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"36481767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM2 promotes p53 ubiquitination and degradation in colorectal cancer cells; CEBPB acts as an upstream transcription factor that binds the TRIM2 promoter and drives its expression in response to epinephrine, linking stress signaling to p53 stability.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for CEBPB binding to TRIM2 promoter, co-immunoprecipitation of TRIM2 with p53, ubiquitination assay, transcriptome sequencing\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — ChIP confirms CEBPB–TRIM2 promoter interaction, Co-IP confirms TRIM2–p53 binding and ubiquitination, single lab\",\n      \"pmids\": [\"35672760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM2 specifically interacts with CPT1A (carnitine O-palmitoyltransferase 1, the rate-limiting enzyme of fatty acid oxidation) and enhances its enzymatic activity, thereby regulating intracellular lipid levels and protecting cancer cells from glutamine deprivation-induced apoptosis; TRIM2 expression in this context is induced by ATF4.\",\n      \"method\": \"Co-immunoprecipitation of TRIM2 with CPT1A, CPT1A enzymatic activity assay, lipid level measurement, TRIM2 knockdown/overexpression with apoptosis and proliferation assays, xenograft tumor growth\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirms interaction, enzymatic activity assay establishes functional enhancement of CPT1A, in vivo xenograft validation, single lab\",\n      \"pmids\": [\"38949993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM2 interacts with CYP11B2 (aldosterone synthase) via its RBCC domain and promotes K29/K48-linked polyubiquitination and proteasomal degradation of CYP11B2, thereby reducing aldosterone production in adrenal tumor cells.\",\n      \"method\": \"siRNA E3 ligase screen, co-immunoprecipitation of TRIM2 with CYP11B2, ubiquitination assay specifying K29/K48 linkages, overexpression assays in adrenal tumor cells measuring aldosterone levels\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirms TRIM2–CYP11B2 interaction, ubiquitination assay defines linkage type, functional readout of aldosterone, single lab\",\n      \"pmids\": [\"39725733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM2 knockdown in endothelial cells attenuates inflammation-driven (but not hypoxia-driven) angiogenesis by reducing nuclear HIF-1α accumulation and downstream eNOS phosphorylation; Trim2-/- mice show reduced adventitial neovascularization in an inflammation model but not in hindlimb ischemia.\",\n      \"method\": \"CRISPR/Cas9 Trim2-/- mice in periarterial collar and hindlimb ischemia models, lentiviral shRNA knockdown in endothelial cells, HIF-1α nuclear fractionation, eNOS phosphorylation Western blot\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in two distinct mouse models plus in vitro mechanistic dissection, single lab\",\n      \"pmids\": [\"38542330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM2 directly interacts with the pro-apoptotic protein BNIP3 and mediates K48-linked polyubiquitination of BNIP3 at lysine 130 (K130), targeting it for proteasomal degradation; mutation K130R abolishes TRIM2-mediated ubiquitination, stabilizes BNIP3, and increases cell death; this TRIM2–BNIP3 axis protects against intestinal ischemia-reperfusion injury.\",\n      \"method\": \"Co-immunoprecipitation of TRIM2 with BNIP3, site-directed mutagenesis (K130R), ubiquitination assay specifying K48 linkage, TRIM2 genetic deletion mouse model, hypoxia/reoxygenation cell death assay\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — Co-IP confirms direct interaction, mutagenesis identifies exact ubiquitination site, K48-linkage specificity established, genetic KO mouse confirms in vivo relevance; multiple orthogonal methods in one study\",\n      \"pmids\": [\"40883557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Using ubiquitin-specific proximity labeling in cells, TRIM2 was found to target proteins of the endolysosomal pathway; specifically, TRIM2 ubiquitinates TMEM106B at lysine residues in its cytosolic N-terminal region. Substrate recognition involves a direct interaction between TRIM2 and a zinc-coordination motif in TMEM106B that mediates homodimerization and is required for lysosomal size regulation. The tripartite motif of TRIM2 (beyond the RING) contributes to substrate recruitment.\",\n      \"method\": \"Ubiquitin-specific proximity labeling (UbID), biochemical pulldown, structural studies, site-directed mutagenesis of TMEM106B lysine residues, lysosomal size assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — proximity labeling substrate discovery combined with structural and biochemical validation plus mutagenesis of ubiquitination sites, multiple orthogonal methods\",\n      \"pmids\": [\"41484378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM2 knockdown and overexpression in primary neurons regulate NF-L protein levels and α-synuclein aggregation, suggesting TRIM2 modulates both substrates relevant to Parkinson's disease neuropathology.\",\n      \"method\": \"Lentiviral knockdown and overexpression in primary neurons, measurement of NF-L levels and α-synuclein aggregation; peripheral proteomic analysis showing increased plasma/CSF NF-L in TRIM2 SNP carriers\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, primary neuron functional assays without in vitro reconstitution, single study with limited mechanistic detail in abstract\",\n      \"pmids\": [\"bio_10.1101_2025.02.21.25322301\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM2 is an m6A-modified substrate of YTHDF3; TRIM2 interacts with and ubiquitinates p53, promoting its degradation via the ubiquitin-proteasome system in uveal melanoma cells.\",\n      \"method\": \"RIP-qPCR confirming m6A modification of TRIM2 by YTHDF3, co-immunoprecipitation of TRIM2 with p53, cycloheximide chase assay demonstrating TRIM2-mediated p53 degradation\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RIP-qPCR for m6A modification, Co-IP for TRIM2–p53 interaction, CHX chase for functional degradation, single lab\",\n      \"pmids\": [\"41391676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystallization of the C-terminal NHL domain of human TRIM2 (residues 465–744) yielded crystals diffracting to 1.7 Å resolution (space group P21), enabling structural characterization of this substrate-recognition domain.\",\n      \"method\": \"Recombinant protein expression/purification, X-ray crystallography, molecular replacement phasing\",\n      \"journal\": \"Acta crystallographica. Section F, Structural biology communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure reported as preliminary (no functional validation of NHL domain function described in abstract, no mutagenesis)\",\n      \"pmids\": [\"24817735\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIM2 is a RING-type E3 ubiquitin ligase that requires UbcH5a as its E2 and functions primarily in neurons, where it ubiquitinates neurofilament light chain (NF-L) to control axonal NF-L levels and neuronal polarity, and ubiquitinates the pro-apoptotic proteins Bim (in a p42/p44 MAPK phosphorylation-dependent manner), BNIP3 (K48-linked at K130), p53, and CYP11B2, as well as the endolysosomal protein TMEM106B; its RING domain dimerization is required for ligase activity, and it possesses a separate antiviral function against New World arenaviruses that is RING-domain independent and mediated partly through interaction with SIRPA.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRIM2 is a RING-type E3 ubiquitin ligase that uses UbcH5a as its cognate E2 and functions prominently in neurons, where it binds and ubiquitinates neurofilament light chain (NF-L) to control axonal NF-L levels, neuronal polarity, and axon specification [#0, #1]; loss of TRIM2 in mice and in humans with biallelic loss-of-function mutations causes early-onset axonal neuropathy with neurofilament accumulation [#0, #3]. Its catalytic competence depends on RING-domain self-association, which a placental-mammal-specific divergence has abolished in the paralog TRIM3, restorable by heterodimerization with TRIM2 through their filamin and coiled-coil domains [#9]. Beyond NF-L, TRIM2 directs ubiquitin-dependent degradation of multiple pro-apoptotic and signaling substrates: it ubiquitinates Bim selectively when Bim is phosphorylated by p42/p44 MAPK, coupling survival signaling to apoptotic control in neuroprotection and tamoxifen-resistant breast cancer [#2, #4]; it mediates K48-linked ubiquitination of BNIP3 at K130 to protect against ischemia-reperfusion injury [#14]; it promotes p53 ubiquitination and degradation [#10, #17]; it drives K29/K48-linked degradation of the aldosterone synthase CYP11B2 [#12]; and it ubiquitinates the endolysosomal protein TMEM106B at cytosolic N-terminal lysines, with substrate recognition mediated by the tripartite motif beyond the RING and by a zinc-coordination motif in TMEM106B that controls lysosomal size [#15]. TRIM2 also possesses a RING-independent antiviral activity that restricts New World arenavirus entry and interacts with SIRPA to limit phagocytosis of apoptotic cells [#5], and it engages the ESCRT component ALIX to regulate neural progenitor survival [#7]. Non-degradative or non-canonical activities have also been described, including stabilization of CPT1A to support fatty acid oxidation [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established TRIM2 as a bona fide E3 ubiquitin ligase and identified NF-L as its substrate, defining a molecular basis for axonal maintenance.\",\n      \"evidence\": \"in vitro ubiquitination with UbcH5a, NF-L co-IP, and TRIM2-knockout mice with axonopathy\",\n      \"pmids\": [\"18687884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin linkage type on NF-L not defined\", \"Whether NF-L degradation is proteasomal not directly shown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected TRIM2-mediated NF-L ubiquitination to the cell-biological decision of axon specification and neuronal polarity.\",\n      \"evidence\": \"RNAi knockdown and overexpression in cultured hippocampal neurons with morphological scoring\",\n      \"pmids\": [\"20796172\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism linking NF-L turnover to polarity not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified Bim as a phosphorylation-gated TRIM2 substrate, coupling MAPK survival signaling to apoptotic regulation in neuroprotection.\",\n      \"evidence\": \"MS substrate ID with phospho-Bim bait, immunodepletion ubiquitination, phosphomutant analysis, neuronal shRNA\",\n      \"pmids\": [\"21478148\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin linkage on Bim not characterized\", \"Structural basis of phospho-dependent recognition unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated that TRIM2 loss causes a human Mendelian axonal neuropathy, validating the mouse model in patients.\",\n      \"evidence\": \"whole-exome sequencing, patient fibroblast protein analysis, sural nerve biopsy\",\n      \"pmids\": [\"23562820\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study\", \"Genotype-phenotype range not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended the TRIM2-Bim axis to cancer, showing GPER/MAPK-driven TRIM2 expression degrades Bim to confer tamoxifen resistance.\",\n      \"evidence\": \"Co-IP, pathway inhibitor dissection, and Bim manipulation in MCF-7/MCF-7R cells\",\n      \"pmids\": [\"28902352\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct ubiquitination in this context not shown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed a RING-independent function: TRIM2 restricts New World arenavirus entry and interacts with SIRPA to limit phagocytosis, separating its antiviral role from ligase activity.\",\n      \"evidence\": \"Trim2-KO mice and patient fibroblasts, RING-domain mutants, interactome, phagocytosis assays\",\n      \"pmids\": [\"30726215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of viral entry restriction unresolved\", \"Whether SIRPA is a ubiquitination substrate unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked TRIM2 to ESCRT machinery via ALIX in neural progenitor survival during neurogenesis.\",\n      \"evidence\": \"GST-Trim2 pulldown with LC-MS/MS in Xenopus and morpholino phenotyping\",\n      \"pmids\": [\"32698497\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab and model organism\", \"Whether ALIX is a substrate or partner not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Reported an unusual deubiquitinating/stabilizing effect of TRIM2 on Snail1 promoting EMT in lung adenocarcinoma.\",\n      \"evidence\": \"Co-IP, Western blot, and ubiquitination assay in lung cancer cell lines\",\n      \"pmids\": [\"32536816\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Deubiquitination claim for a RING E3 is mechanistically unusual and not validated by orthogonal methods\", \"No reciprocal validation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Genetic allele comparison suggested the axonopathy phenotype may not require full ligase activity, complicating the catalytic model.\",\n      \"evidence\": \"CRISPR Trim2-null versus partial RING-deletion mouse strains with neuropathology\",\n      \"pmids\": [\"32205255\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Residual ligase activity in deletion allele not quantified mechanistically\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Structurally explained TRIM2 RING-dimerization dependence and showed TRIM2 can restore the inactive paralog TRIM3 via heterodimerization.\",\n      \"evidence\": \"RING domain structure-function, mutagenesis, in vitro E3 assays, cellular Co-IP\",\n      \"pmids\": [\"36481767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequences of TRIM2-TRIM3 heterodimers in vivo not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed TRIM2 in a stress-signaling axis where CEBPB drives TRIM2 expression to degrade p53 in colorectal cancer.\",\n      \"evidence\": \"ChIP for CEBPB-promoter binding, Co-IP, ubiquitination assay, RNA-seq\",\n      \"pmids\": [\"35672760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin linkage on p53 not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a non-degradative metabolic role: TRIM2 binds and enhances CPT1A activity to support fatty acid oxidation and survival under glutamine deprivation.\",\n      \"evidence\": \"Co-IP, CPT1A activity and lipid assays, xenograft growth, ATF4 induction\",\n      \"pmids\": [\"38949993\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of enzymatic enhancement unknown\", \"Whether ubiquitination is involved unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined TRIM2 control of aldosterone synthesis via K29/K48-linked degradation of CYP11B2.\",\n      \"evidence\": \"siRNA E3 screen, Co-IP, linkage-specific ubiquitination, aldosterone measurement in adrenal tumor cells\",\n      \"pmids\": [\"39725733\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Physiological regulation of this axis not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated a context-specific vascular role for TRIM2 in inflammation-driven angiogenesis through HIF-1\\u03b1 and eNOS signaling.\",\n      \"evidence\": \"Trim2-/- mice in two models, endothelial shRNA, HIF-1\\u03b1 fractionation, eNOS phosphorylation\",\n      \"pmids\": [\"38542330\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate in endothelial cells not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved a precise degron, identifying K48-linked ubiquitination of BNIP3 at K130 as a protective axis in intestinal ischemia-reperfusion.\",\n      \"evidence\": \"Co-IP, K130R mutagenesis, K48-linkage ubiquitination assay, KO mouse, hypoxia/reoxygenation death assay\",\n      \"pmids\": [\"40883557\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this axis operates in non-intestinal tissues unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected TRIM2 to m6A regulation (YTHDF3) and reaffirmed p53 as a degradation substrate in uveal melanoma.\",\n      \"evidence\": \"RIP-qPCR for m6A, Co-IP, cycloheximide chase\",\n      \"pmids\": [\"41391676\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin linkage on p53 not specified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Used unbiased proximity labeling to place TRIM2 in the endolysosomal pathway, identifying TMEM106B as a substrate and defining tripartite-motif-mediated, structure-based substrate recognition.\",\n      \"evidence\": \"ubiquitin-specific proximity labeling, biochemical pulldown, structural studies, TMEM106B lysine mutagenesis, lysosomal size assays\",\n      \"pmids\": [\"41484378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Linkage type on TMEM106B not detailed\", \"Physiological role in lysosomal regulation in vivo not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how TRIM2 selects among its diverse substrates across neurons, immune cells, endothelium, and tumors, and how its RING-dependent ligase activity, RING-independent antiviral function, and non-degradative metabolic roles are coordinated within a single protein.\",\n      \"evidence\": \"no single study integrates the divergent functional contexts\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying model of substrate selection\", \"Tissue-specific cofactors unknown\", \"Relationship between catalytic and non-catalytic functions undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 12, 14, 15]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 12, 14]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 14, 15]},\n      {\"term_id\": \"GO:0031386\", \"supporting_discovery_ids\": [14, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 15]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 12, 14, 15]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NEFL\", \"BCL2L11\", \"BNIP3\", \"TP53\", \"CYP11B2\", \"TMEM106B\", \"SIRPA\", \"CPT1A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}